Type II diabetes is the most common form of diabetes accounting for 90% of diabetes cases. Over 100 million people worldwide have type-2 diabetes (nearly 17 million in the U.S.) and the prevalence is increasing dramatically in both the developed and developing worlds. Type-II diabetes is a lifelong illness, which generally starts in middle age or later part of life, but can start at any age. Patients with type-2 diabetes do not respond properly to insulin, the hormone that normally allows the body to convert blood glucose into energy or store it in cells to be used later. The problem in type-2 diabetes is a condition called insulin resistance where the body produces insulin, in normal or even high amounts, but certain mechanisms prevent insulin from moving glucose into cells. Because the body does not use insulin properly, glucose rises to unsafe levels in the blood.
Over time, sustained hyperglycemia leads to glucotoxicity, which worsens insulin resistance and contributes to dysfunction in the beta cells of the pancreas. The degree of sustained hyperglycemia is directly related to diabetic microvascular complications and may also contribute to macrovascular complications. In this way, hyperglycemia perpetuates a cycle of deleterious effects that exacerbate type 2 diabetes control and complications.
It is now widely accepted that glycemic control makes a difference in type II diabetes patients. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications associated with elevated glucose in the blood. Oral therapeutic options for the treatment of type II diabetes mellitus include compounds known as: sulfonylureas, biguanides (metformin), thiazolidinediones, and alpha-glucosidase inhibitors. The active agents from each class are generally administered to patients alone. However, once monotherapy becomes inadequate, combination therapy is an attractive and rational course of action for treating hyperglycemia.
Recently, a new class of anti-diabetics was discovered known as sodium-glucose transporter-2 inhibitors (SGLT2). SGLT2 inhibitors prevent the reabsorption of glucose into blood by the kidney. The kidney, at first, allows glucose to pass from the blood into the bladder. Once in the urine, however, glucose is reabsorbed back into the blood via the renal proximal tubules. Ninety percent of glucose reuptake in the kidney occurs in via the renal proximal tubules. SGLT2 is a protein predominantly expressed in the renal proximal tubules and is likely to be the major transporter responsible for this reuptake.
Accordingly, the present invention provides pharmaceutical formulations that comprise metformin and an SGLT2 inhibitor, such as dapagliflozin, for oral administration in the treatment of diseases or disorders associated with SGLT2 activity. The metformin/SGLT2 formulations of the present invention provide an antidiabetic therapy to patients that is both convenient and effective for controlling blood glucose levels.
However, to successfully formulate a pharmaceutical composition comprising the combination of dapagliflozin or dapagliflozin (S) propylene glycol hydrate and metformin into granules or into a tablet formulation is challenging for several reasons.
Firstly, the large drug-to-drug ratio between metformin and the SGLT2 inhibitor makes content uniformity, with respect to dapagliflozin or dapagliflozin (S) propylene glycol hydrate in the final formulation, an important issue. It is necessary to have this relatively small amount of dapagliflozin or dapagliflozin (S) propylene glycol hydrate evenly distributed throughout the final granules or tablet formulation and thus avoid any variation in content.
In addition, the large difference in physical properties between dapagliflozin or dapagliflozin (S) propylene glycol hydrate and metformin, and especially the poor compaction properties of metformin, make it difficult to produce tablets having acceptable mechanical strength.
After several unsuccessful attempts, including dry granulation by roller compaction and traditional wet granulation, it has now been found that both of the above requirements can be met by spraying a solution or a suspension comprising dapagliflozin or dapagliflozin (S) propylene glycol hydrate and a binder onto the metformin particles in a fluid bed equipment, thereby producing granules that have uniform dapagliflozin or dapagliflozin (S) propylene glycol hydrate content and good compaction properties. The good compaction properties of these granules are thought to result from the way the granules are formed during the spray granulation process together with the fact that this process makes it possible to use larger amounts of a binder than was possible in the earlier tested granulation processes. The way in which the granules are built up during the spray granulation process gives them suitable density/porosity and a suitable particle size distribution with little variation between batches. The granules also have superior flow properties.
It has further been found that these beneficial formulations can be achieved while maintaining the chemical stability of the dapagliflozin or dapagliflozin (S) propylene glycol hydrate despite using a process in which at least part of the dapagliflozin is dissolved in water.